Rho-associated protein kinase (ROCK) is a member of the serine-threonine protein kinase family. ROCK, which exists in two isoforms, ROCK1 and ROCK2, is an effector molecule of RhoA, and the RhoA/ROCK signaling pathway is involved in a number of cellular functions, which include, for example, actin organization, cell adhesion, cell migration, and cytokinesis. In addition, the RhoA/ROCK signaling pathway is involved in regulating smooth muscle contraction. Inhibitors of ROCK have been reported to be useful for treating multiple medical disorders, such as fibrosis, inflammatory disorders, autoimmune disorders, and cardiovascular disorders.
Fibrosis is a condition featuring excess fibrotic connective tissue, which may form in numerous types of bodily tissues, including, for example, skin, lung, kidney, heart, liver, and gastrointestinal tract. Exemplary fibrotic disorders include scleroderma, kidney fibrosis, pulmonary fibrosis, liver fibrosis, cardiac fibrosis, and skin fibrosis. Scleroderma is frequently characterized as featuring increased synthesis of collagen, and the disease typically features hardening of the skin, and in more severe forms of the disease may also affect internal organs. Pulmonary fibrosis involves scarring of lung tissue, which can occur when alveoli and interstitial tissue of the lungs become inflamed and develop scars in an attempt to repair themselves. Pulmonary fibrosis can be caused by various conditions which include chronic inflammatory processes, infections, environmental agents (e.g., asbestos or silica), exposure to ionizing radiation, and even certain medications (e.g., pingyangmycin, busulfan, methotrexate, and nitrofurantoin). Cystic fibrosis is a type of pulmonary fibrosis. Liver fibrosis typically involves excessive accumulation of extracellular matrix proteins in the liver, and the subsequent scarring process. Over time, advanced liver fibrosis can result in cirrhosis of the liver. Cardiac fibrosis can involve a disproportionate accumulation of fibrillated collagen that can occur after myocyte death, inflammation, enhanced workload, hypertrophy, and/or stimulation by a number of hormones, cytokines, and growth factors. Cardiac fibrosis may contribute to sudden cardiac death, ventricular tachyarrhythmia, left ventricular (LV) dysfunction, and heart failure.
Inflammatory disorders that continue to afflict a significant number of people include psoriasis and nonalcoholic steatohepatitis. Psoriasis is a chronic, inflammatory, hyperproliferative skin condition. It has been reported that approximately 150,000 new cases of psoriasis and approximately 400 deaths from psoriasis are reported each year. See Stern, R. S. (1995) Dermatol. Clin. 13:717-722. Typical symptoms of psoriasis include skin lesions, redness, inflammation, or patches of skin that become dry, red, covered with silvery scales, cracked, and/or painful. Psoriasis can affect all parts of the skin, but it is more commonly seen on the skin of the trunk, scalp, elbows, knees, or in the fingernails or toenails. The symptoms of psoriasis may become worse in response to cuts, burns, insect bites or other skin injuries. The symptoms of psoriasis can also be more severe in patients having a deficient immune system, such as patients afflicted with AIDS or receiving cancer chemotherapy. Amongst the several types of psoriasis, the most common type of psoriasis is chronic plaque syndrome. This type of psoriasis consists of periods of remission and relapse during the course of the condition. If left untreated, plaque psoriasis can evolve into a more severe condition, such as pustular psoriasis or erythrodermic psoriasis. Current treatment options for psoriasis include acitretin, cyclosporine, methotrexate, apremilast, phototherapy, and biologics such as anti-TNF antibodies adalimumab, etanercept, and the anti-IL12/IL23 antibody ustekinumab. However, these treatments do not meet the needs of all patients suffering from psoriasis, and thus the need exists for new therapeutic agents for treating psoriasis and other inflammatory disorders.
Nonalcoholic steatohepatitis (NASH) is a liver disorder featuring inflammation and damage associated with buildup of fat in the liver. A significant percentage of patients suffering from NASH are approximately forty to fifty years old and also suffer from obesity, insulin resistance, high cholesterol, and/or metabolic syndrome. Diagnostic tests for identifying NASH include histological evaluation of a liver biopsy, and patients suffering from NASH may experience right upper quadrant pain, hepatomegaly, or non-specific symptoms such as abdominal discomfort, weakness, fatigue, and/or malaise. Treatment options for NASH are quite limited and new therapeutic agents are needed.
Accordingly, a need exists for improved treatments for inflammatory and other medical disorders. The present invention addresses this need and provides other related advantages.